PBPK‐led assessment of antimalarial drugs as candidates for Covid‐19: Simulating concentrations at the site of action to inform repurposing strategies

Abstract The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID‐19) prompted a global effort to evaluate drug repurposing opportunities. Pyronaridine and amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). In vitro activity does not always translate to clinical efficacy across a therapeutic dose range. This study applied available, verified, physiologically based pharmacokinetic (PBPK) models for pyronaridine, amodiaquine, and its active metabolite N‐desethylamodiaquine (DEAQ) to predict drug concentrations in lung tissue relative to plasma or blood in the default healthy virtual population. Lung exposures were compared to published data across the reported range of in vitro EC50 values against SARS‐CoV‐2. In the multicompartment permeability‐limited PBPK model, the predicted total C max in lung mass for pyronaridine was 34.2 μM on Day 3, 30.5‐fold greater than in blood (1.12 μM) and for amodiaquine was 0.530 μM, 8.83‐fold greater than in plasma (0.060 μM). In the perfusion‐limited PBPK model, the DEAQ predicted total C max on Day 3 in lung mass (30.2 μM) was 21.4‐fold greater than for plasma (1.41 μM). Based on the available in vitro data, predicted drug concentrations in lung tissue for pyronaridine and DEAQ, but not amodiaquine, appeared sufficient to inhibit SARS‐CoV‐2 replication. Simulations indicated standard dosing regimens of pyronaridine‐artesunate and artesunate‐amodiaquine have potential to treat COVID‐19. These findings informed repurposing strategies to select the most relevant compounds for clinical investigation in COVID‐19. Clinical data for model verification may become available from ongoing clinical studies.

) and Cmin values are pre-dose for the third dose on Day 3 (lowest value between 24 and 48 h) for pyronaridine and amodiaquine in the permeability-limited PBPK model.Values are means (5 th percentile, 95 th percentile).ELF, epithelial lining fluid; L:B, lung-to-blood ratio; L:P, lung-to-plasma ratio; UB, unbound.a Altered physiological parameters with COVID-19 were lung pH of 6, plasma levels of alpha 1-acid glycoprotein (AAG) of 1.695 g/dL, and plasma levels of human serum albumin (HSA) was 40 g/dL.As a metabolite, the parameters cannot be varied for N-desethylamodiaquine (DEAQ) in the perfusion-limited PBPK model.

FIGURE S1.
Analysis at lung pH observed in COVID-19 patients (pH 6).Simulated total concentrations in lung mass and epithelial lining fluid, unbound concentrations in lung mass, and total concentrations in blood or plasma for A) pyronaridine using the permeability limited PBPK model; and B) amodiaquine using the permeability limited PBPK model.2) for A) pyronaridine; and B) amodiaquine.
Values are mean and whiskers are the 5 th and 95 th percentiles.Values are mean and whiskers are the 5 th and 95 th percentiles.

FIGURE S2 .
FIGURE S2.Analysis at lung pH observed in.Ratio of predicted Day 3 trough concentrations in the lung mass relative to the respective reported EC/IC50 values against SARS-CoV-2 (Table2) for A) pyronaridine; and B) amodiaquine.

TABLE S1 .
Analysis of adjusted pH and plasma proteins based on COVID-19 disease state.Predicted blood or plasma and lung concentrations for pyronaridine and amodiaquine in the permeabilitylimited PBPK model.

Compartment Diseased lung pH a Diseased lung pH, AAG, HSA a Pyronaridine Cmax, µM Cmin, µM Cmax, µM Cmin, µM
FIGURE S3.Analysis at lung pH observed in COVID-19 patients (pH 6), plus plasma proteins adjusted based on values from COVID-19 patients for alpha 1-acid glycoprotein (1.695 g/dL), and human serum albumin (40 g/dL).Simulated total concentrations in lung mass and epithelial lining fluid, unbound concentrations in lung mass, and total concentrations in blood or plasma for A) pyronaridine using the permeability limited PBPK model; and B) amodiaquine using the permeability limited PBPK model.Analysis at lung pH observed in COVID-19 patients (pH 6), plus plasma proteins adjusted based on values from COVID-19 patients for alpha 1-acid glycoprotein (1.695 g/dL), and human serum albumin (40 g/dL).Ratio of predicted Day 3 trough concentrations in the lung mass relative to the respective reported EC/IC50 values against SARS-CoV-2 (Table2) for A) pyronaridine; and B) amodiaquine.